Clinical Lab Director’s View Part 1: Launching a New Genetic Test

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Today we kick off a new series of blog posts focusing on the challenges associated with the interpretation and reporting of NGS-based diagnostic tests. We’ve been thinking about this a lot lately as clinical labs engage with our new Clinical Decision Support platform through the early access program. The platform is designed to help clinical labs scale their NGS-based test offerings, saving time and accelerating results.

Junaid Shabbeer, QIAGEN Bioinformatics’ Clinical Science Director

Junaid Shabbeer, QIAGEN Bioinformatics’ Clinical Science Director

In this arena we rely heavily on people like Junaid Shabbeer, a board-certified lab director and QIAGEN Bioinformatics’ Clinical Science Director, to gather a more comprehensive understanding of clinical labs’ unmet needs, requirements, and challenges — and make sure that our new platform addresses those. We recently sat down with Junaid to get a better handle on the opportunities and challenges related to NGS genetic testing interpretation and reporting , and throughout this blog series we’ll relate the great insights he shared with us. In today’s post we take a look at the components that go into designing, building, and launching a new genetic test for a lab. Junaid is a good guide for us, given his experience in directing clinical labs at Mount Sinai Hospital in New York, Myriad Genetics, and most recently Ariosa Diagnostics.

Launching the Test

Setting up a new assay is certainly not easy, Junaid tells us — but there are established strategies and steps that labs can follow, as well as guidelines from professional organizations such as ACMG and CAP. At the early test development stage, lab directors gather information on genes known to be associated with a disease they want to test for. Next, they’ll design an assay and choose a platform that will ensure the best performance for the test, for example one that provides uniform coverage of the genes. The aim is for the lab to be able to offer a test with good sensitivity and specificity to find important genetic variants.

“When it comes to designing the assay, you need to make sure it covers enough of the gene, or targets specific regions of the gene where the majority of relevant variants are known to be located,” Junaid says. Next-gen sequencing enables full coverage of multiple genes in a single test, ensuring that variants will be detected no matter where in the genes they may fall. Such tests, though, have unique challenges when it comes to ensuring the robustness and quality of results. For example, depth of sequencing is a very important factor in determining whether a variant found in the assay is real or not.

“There are several commercially available ways of amplifying and sequencing a gene,” Junaid says. “The onus is on the clinical lab to validate the assay.” This entails running a number of samples with known variants to make sure the new assay is picking up everything it should be — and nothing it shouldn’t.

The Variant Universe

Of course, part of laying the groundwork for the new test is getting a sense of the number and types of variants this assay will detect in order to plan for result interpretation needs. For well-established cancer driver mutations, like BRAF V600E or EGFR exon 19 deletions, lab directors could conceivably automate variant interpretation and reporting for these mutations. But for rarer cancer variants, the interpretation and reporting will necessarily be customized for each and every sample that comes through the door. Junaid says that while it is ideal to have a variant analyst who specializes in the genes and diseases the new assay will evaluate, the reality is that, for the most part, “a gene is a gene. The same core principles and techniques would be used to score variants for a new assay.” Smaller reference labs in particular, he notes, are unlikely to have the luxury of hiring analysts with expertise in each and every disease their assays cover.

The Report

Before the assay can be run for patients, the lab director must make important decisions about what the test report will look like — what information it will include, how pathogenic or actionable variants will be highlighted, and more. For diseases associated with a small number of genes, such as Lynch syndrome, directors will usually include all variants found in the final report, Junaid says. Assays screening larger number of genes may not be conducive to that kind of report, so in those cases lab directors may choose not to include variants that are commonly seen in the general population (and therefore likely benign) or that are already well-known not to confer risk for the disease. Variants that are known or likely to be pathogenic or actionable will be highlighted and annotated with information about the risk classification.

Of course, clinical lab regulations dictate the minimal information that will appear on the report, such as details about the test performed or important notes on the assay or platform used. Reports may also include guidance notes on the clinical significance of pathogenic variants and advice on treatment options.

Validation

Extensive validation studies must be conducted by the laboratory before a new test is offered for patient testing. These include internal concordance tests to ensure the right result is obtained for samples with known variants. The lab must also perform proficiency testing in accordance with clinical lab standards at least annually to make sure the assay continues to perform as expected. Junaid notes that ACMG, CAP, and other professional organizations offer extensive guidelines and support for laboratories about test requirements and what to include in a validation. “Fortunately, there are a lot of guidance documents,” he says.

Check back soon as we post the next couple of installments of our series on how clinical labs handle genetic tests and variant interpretation.  Be sure to visit our booth (# 707 and #1023) and workshop next week at the upcoming annual meeting of the Association for Molecular Pathology in National Harbor, Md. Junaid Shabbeer will be at AMP 2014 and would be happy to answer any questions you may have.

Next Blog: Clinical Lab Director’s View Part 2: Scoring a Variant